Bacillus anthracis is perhaps the most deadly of potential bioweapons, because the spores can be produced in a form that can be readily aerosolized for inhalation deep into the vulnerable airspaces of the lung, causing the devastating disease, inhalation anthrax. Our understanding of the basic immunopathology that occurs in the lung after spore inhalation is incredibly poor. Knowledge of how the lung responds to inhaled spores and the inflammatory events that follow during germination and dissemination, along with which virulence factors play a role in escape from the lung, survival of the pathogen and damage to the host after dissemination are all prerequisites for development of effective therapeutic and vaccination strategies. Moreover, we need to understand the host responses that are responsible for enhancing host resistance to B. anthracis. Our first hypothesis is that murine and cynomolgus host permissiveness for systemic spread following pulmonary B. anthracis spore deposition is dictated by the ability of the organism to express capsule in the lungs and regional lymphoid tissues. Our second hypothesis is that lung macrophage dysfunction and C5 deficiency place the host at increased risk of dying from a pulmonary anthrax infection. Specifically we will: Aim 1. Assess the roles of important B. anthracis virulence factors in a pulmonary infection in mice, using a virulent B. anthracis strain, UT500, and deletion mutants of UT500 that fail to express lethal factor (LF), edema factor (EF), LF+EF, or capsule. We will then compare the role of these virulence factors in a systemic infection by inoculating the vegetative forms of each of the five strains directly into the bloodstream. Aim 2. Determine the roles for alveolar macrophages and complement in early pulmonary defenses and dissemination of virulent B. anthracis in mice, and assess the role of antibody to capsule and toxin in protection. Aim 3. Assess the roles of important B. anthracis virulence factors in an aerosol infection in cynomolgus monkeys by comparing lung infections with virulent UT500 and the LF, EF, LF+EF and capsule deletent mutants. We will then compare the role of these virulence factors in a systemic infection induced by IV inoculation with vegetative forms of each of the five strains.